An Artificial Capillary in Vitro Kinetic Model of Antibiotic Bactericidal Activity

Zinner, Stephen H.; Husson, M.; Klastersky, Jean

doi:10.1093/infdis/144.6.583

Cited by 24 publications

(17 citation statements)

References 12 publications

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“…Several experimental setups and membrane types have been described, including systems with artificial or natural membranes (Gloede et al, 2010). With the single-membrane system (Bonapace et al, 2002), a slow equilibration process is obtained generally resulting in two-compartment kinetics in the peripheral compartment (Zinner et al, 1981).…”

Section: A Experimental In Vitro Systemsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

2013

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Section: A Experimental In Vitro Systemsmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

2013

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“…Several in vitro pharmacokinetic models to simulate human pharmacokinetics have been described, based on either dilution (3,4,16,17,20,23, 26,28,32) or diffusion (1,5,12,34,39). We developed an in vitro pharmacodynamic model based on a dialyzer unit, which is described here.…”

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confidence: 99%

Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model

Mouton

Hollander

1994

Antimicrob Agents Chemother

260

197

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An in vitro pharmacokinetic model mimicking human serum drug concentrations, based on a dialyzer unit, was developed to study the efficacies of continuous infusion and intermittent administration of ceftazidime over a period of 36 h. The daily dose of ceftazidime was 300 mg/liter/24 h given either as a continuous infusion or as three bolus doses. The intermittent dosing regimen yielded peak and trough concentrations after the fourth dose of 92.3 (standard deviation, 8.0) and 1.4 (standard deviation, 0.9) mg/liter, respectively. Continuous administration yielded concentrations of approximately 20 mg/liter. To study efficacy, three Pseudomonas aeruginosa strains, ATCC 27853, CF4, and CF16, were used. The MICs of ceftazidime for these strains were 1, 4, and 16 mg/liter, respectively. Strain CF16 was killed initially during both regimens and then started to regrow. At the end of the fourth dosing interval, i.e., after 32 h, viable counts showed no difference between the regimens. Strains ATCC 27853 and CF4 were killed initially during both dosing schedules, and after the first dosing interval viable counts were similar. However, after the fourth interval, there was a marked difference between bacterial counts during continuous and intermittent infusion, being 2.2 and 2.8 loglo, respectively, demonstrating a greater efficacy during continuous infusion. The results indicate that, in the absence of other factors, a sustained level of ceftazidime around or slightly above the MIC is not high enough to maintain efficacy over more than one (8-h) dosing interval. When sustained concentrations higher than four times the MIC are employed, continuous administration in this model is more efficacious than intermittent dosing.Time-kill curves for beta-lactam antibiotics against Pseudomonas aeruginosa show time-dependent killing which is maximal at relatively low concentrations (35). Concentrations much higher than the MIC contribute no extra effect. From these experiments, it can be deduced that continuous serum drug concentrations above the MIC of the antibiotic used to combat the microorganism in question should be more efficacious than declining concentrations, as observed after intermittent dosing (8, 10). During the latter regimen, concentrations fall below the MIC during part of the dosing interval. It has been shown in several animal models that continuous infusion is indeed more efficacious than intermittent dosing (14,21, 27). However, the half-life of most drugs is severely shortened in the animals studied, and conclusions regarding the pharmacodynamics in humans are difficult to make (15). For, if the shortened half-life is taken into account, the time during which the concentration is below the MIC applies for almost the entire dosing interval, which is contrary to the situation as observed in humans. This problem has, however, been partly overcome by fractional dosing to mimic human pharmacokinetics (13).In vitro simulation of human pharmacokinetics may thus give additional information with respect to kinetics of kil...

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“…The two-compartment capillary model presented here is designed for multiple cultures and did not result in dilution of the bacterial inoculum. This model represents several modifications of the artificial capillary unit model described previously (29) and allowed for continuous drug elimination, homogeneous drug concentration in the peripheral compartments, and the study of several organisms simultaneously.…”

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confidence: 99%

Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model

Blaser¹,

Stone²,

Zinner³

1985

Antimicrob Agents Chemother

100

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Several aminoglycoside dosage regimens were studied in a kinetic in vitro model. Pseudomonas aeruginosa, Escherichia coli, Klebsieila pneumoniae, and Staphylococcus aureus were exposed in serially placed artificial capillary units to netilmicin concentrations that changed based on human two-compartment pharmacokinetics. The same total dose per 24 h was administered as a continuous infusion (3.7 ,ug/ml) or in 1-h infusions given every 24 (24 ,.g/ml) or 8 h (8 ,Lg/ml). The once daily administration showed the best response in terms of either faster killing of E. coli, K. pneumoniae, and S. aureus or greater reduction of the inocula ofP. aeruginosa. After 28 h of treatment, however, all regimens reduced the nonpseudomonads by more than 99.99%, whereas all three P. aeruginosa strains regrew to >108 CFU/ml due to selection of resistant subpopulations. In contrast to the bactericidal effect of the first dose, no killing occurred after subsequent doses if the ratio of peak drug concentration to MIC was low (c6). These results support the concept of administering high doses of aminoglycosides once every 24 h.

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An Artificial Capillary in Vitro Kinetic Model of Antibiotic Bactericidal Activity

Cited by 24 publications

References 12 publications

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model

Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model

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